Sequential enhancer state remodelling defines human germline competence and specification

Walfred W C Tang* (Corresponding Author), Aracely Castillo-Venzor, Wolfram H Gruhn, Toshihiro Kobayashi, Christopher A Penfold, Michael D Morgan, Dawei Sun, Naoko Irie, M Azim Surani* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Germline-soma segregation is a fundamental event during mammalian embryonic development. Here we establish the epigenetic principles of human primordial germ cell (hPGC) development using in vivo hPGCs and stem cell models recapitulating gastrulation. We show that morphogen-induced remodelling of mesendoderm enhancers transiently confers the competence for hPGC fate, but further activation favours mesoderm and endoderm fates. Consistently, reducing the expression of the mesendodermal transcription factor OTX2 promotes the PGC fate. In hPGCs, SOX17 and TFAP2C initiate activation of enhancers to establish a core germline programme, including the transcriptional repressor PRDM1 and pluripotency factors POU5F1 and NANOG. We demonstrate that SOX17 enhancers are the critical components in the regulatory circuitry of germline competence. Furthermore, activation of upstream cis-regulatory elements by an optimized CRISPR activation system is sufficient for hPGC specification. We reveal an enhancer-linked germline transcription factor network that provides the basis for the evolutionary divergence of mammalian germlines.

Original languageEnglish
Pages (from-to)448-460
Number of pages13
JournalNature Cell Biology
Issue number4
Early online date11 Apr 2022
Publication statusPublished - 11 Apr 2022

Bibliographical note

M.A.S. was supported by Wellcome Investigator Awards in Science (209475/Z/17/Z and 096738/Z/11/Z), an MRC research grant (RG85305) and a BBSRC research grant (G103986). W.W.C.T. received a Croucher Postdoctoral Research Fellowship and was supported by the Isaac Newton Trust. A.C.-V. was supported by the Wellcome 4-Year PhD Programme in Stem Cell Biology and Medicine and the Cambridge Commonwealth European and International Trust (203831/Z/16/Z). W.H.G. was supported by a BBSRC research grant (G103986). T.K. and M.A.S. were supported by Butterfield Awards of Great Britain Sasakawa Foundation. T.K. was supported by the Astellas Foundation for Research on Metabolic Disorders. D.S. was supported by a Wellcome
Trust PhD studentship (109146/Z/15/Z) and the Department of Pathology, University of Cambridge. N.I. was supported by an MRC research grant (RG85305). We thank R. Barker and X. He for providing human embryonic tissues, and C. Bradshaw for bioinformatic support. We also thank The Weizmann Institute of Science for the WIS2 hESC line and the Genomics Core Facility of CRUK Cambridge Institute for sequencing services, and R. Alberio and members of the Surani lab for insightful comments and critical reading of the manuscript.

Data Availability Statement

Data availability
ChIP–seq and RNA-seq datasets are available on NCBI GEO (GSE159654). Single-cell sequencing datasets are available on ArrayExpress (E-MTAB-11135). Previously published data that were re-analysed here are: hPGC RNA-seq (GSE60138), TF KO RNA-seq (GSE99350), TFAP2C ChIP–seq (GSE140021) and OTX2 ChIP–seq (GSE61475). Genome databases used are: UCSC GRCh38/hg38, Ensembl GrCh38 v90 and Gencode Human Release 30. All other data supporting the findings of this study are available from the corresponding authors on reasonable request. Source data are provided with this paper.

Extended data is available for this paper at

Supplementary information
The online version contains supplementary material
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  • Animals
  • Cell Differentiation/genetics
  • Embryonic Development/genetics
  • Endoderm
  • Gastrulation
  • Gene Expression Regulation, Developmental
  • Germ Cells/metabolism
  • Humans
  • Mammals


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